Routine-grade performance of a new static headspace autosampler for the analysis of residual solvents according to USP <467> method

Importance of the Topic

Residual solvents are critical quality attributes in pharmaceutical manufacturing. Incomplete removal of these volatile organic compounds can pose significant health hazards. The USP <467> guideline establishes concentration limits and classifies solvents by toxicity, making robust analytical methods essential for ensuring product safety and regulatory compliance.

Objectives and Study Overview

This work evaluated the performance of the Thermo Scientific TriPlus 500 static headspace autosampler coupled with a TRACE 1310 GC and FID detector for USP <467> residual solvent analysis. The study assessed system suitability, sensitivity, precision, robustness, linearity, and overall compliance for both water-soluble and water-insoluble pharmaceutical matrices.

Methodology

The USP <467> procedures A, B, and C were followed:

• Procedure A: Screening and identification of residual solvents in unspiked and spiked samples.
• Procedure B: Peak identity confirmation using a polar WAX column for critical pair resolution.
• Procedure C: Quantification of confirmed residual solvents across a defined calibration range.

Sample preparation involved dilution of Class 1, 2A, and 2B solvent standards in water or DMSO, with test solutions spiked into aspirin and paracetamol tablets.

Instrumentation Used

• TriPlus 500 Headspace Autosampler
• Thermo Scientific TRACE 1310 Gas Chromatograph
• Instant Connect Split/Splitless SSL Injector
• Instant Connect Flame Ionization Detector (FID)
• TraceGOLD TG-624 GC Column (30 m × 0.32 mm × 1.8 µm) for procedures A/C
• TraceGOLD TG-WAXMS GC Column (30 m × 0.32 mm × 0.25 µm) for procedure B
• Chromeleon CDS Software v7.2 for data acquisition and processing

Key Results and Discussion

System suitability criteria were consistently met:

• Peak-to-peak signal-to-noise ratios exceeded USP thresholds (PtP S/N > 5:1 for Class 1 solvents, > 3:1 for others).
• Chromatographic resolution (Rs) between critical pairs such as acetonitrile/dichloromethane and cis-1,2-dichloroethene/acetonitrile was > 1.0, often exceeding 3.0 on the WAX column.
• Repeatability demonstrated average peak area RSDs < 3% over 18 injections for all solvent classes, with slightly improved precision when using DMSO diluent for apolar analytes.
• Linearity was confirmed across 12.5–100% of concentration limits, yielding average R² = 0.998 and residual RSDs < 8%.

Benefits and Practical Application

• The direct heated valve-to-column flow path and continuous purge design deliver excellent robustness and low carryover.
• Automated e-workflows in Chromeleon CDS streamline sequence setup, result calculation, and compliance with 21 CFR Part 11.
• The system supports efficient screening, confirmation, and quantification in a single platform, reducing laboratory workload and turnaround time.

Future Trends and Opportunities

Advances in headspace automation and improved detector sensitivity may enable lower detection limits and expanded analysis of emerging volatile impurities. Integration with high-throughput platforms and cloud-based data management will further enhance laboratory efficiency and regulatory traceability.

Conclusion

The TriPlus 500 HS autosampler combined with TRACE 1310 GC-FID and Chromeleon CDS provides a complete solution for USP <467> residual solvent testing. The system meets or exceeds all USP criteria for sensitivity, precision, resolution, linearity, and robustness, making it well suited for routine pharmaceutical quality control.

References

1. United States Pharmacopeia. USP <467> Organic Volatile Impurities, 2012.
2. ICH Guideline Q3C(R6) Impurities: Residual Solvents, 2016.
3. Thermo Fisher Scientific. Chromeleon CDS Enterprise – BR72617-EN 0718S.
4. United States Pharmacopeia. USP <621> Chromatography, 2017.